| Literature DB >> 34861191 |
Charly R Good1, M Angela Aznar2, Shunichiro Kuramitsu2, Parisa Samareh1, Sangya Agarwal3, Greg Donahue1, Kenichi Ishiyama4, Nils Wellhausen2, Austin K Rennels2, Yujie Ma2, Lifeng Tian5, Sonia Guedan2, Katherine A Alexander1, Zhen Zhang1, Philipp C Rommel2, Nathan Singh2, Karl M Glastad1, Max W Richardson6, Keisuke Watanabe2, Janos L Tanyi7, Mark H O'Hara8, Marco Ruella9, Simon F Lacey5, Edmund K Moon10, Stephen J Schuster11, Steven M Albelda10, Lewis L Lanier4, Regina M Young12, Shelley L Berger13, Carl H June14.
Abstract
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.Entities:
Keywords: CAR T cell; ID3; NK-like T cell; SOX4; T cell dysfunction; T cell exhaustion; cancer; cell transfer therapy; immunology; immunotherapy; pancreatic cancer; single-cell RNA-seq
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Year: 2021 PMID： 34861191 PMCID： PMC8827167 DOI： 10.1016/j.cell.2021.11.016
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850